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Genetic counseling: Ehlers-Danlos Syndrome
Ehlers-Danlos Syndrome Contracting *Introductions, acknowledge any prior contact *Assess main concerns of patient **Why are they visiting Genetics today? **What do they hope to gain from the session? **Assess knowledge of diagnosis -- any questions? *Overview of today's session **Restate patient's concerns **Medical history, family history, physical exam, genetics, recurrence risk, testing options and limitations Pediatric Intake *Pregnancy and Medical History **umbilical/unguinal hernia? prematurity? cervical incompetence? *Developmental History **learning disabilities? *Family History **heart problems? joint hypermobility? stretchy skin? fragile skin? easy to scar? scoliosis? easy bruising? congenital hip dislocations? stroke? umbilical/inguinal hernias? early loss of teeth? Incidence and Carrier Frequency *no well-founded figures for prevalence *for all forms, estimates of 1/5000 have been made Clinical Features ** a group of clinically diverse inherited connective tissue disorders that have joint laxity and dermal features in common ** *Classical (Type I and Type II) **Major diagnostic criteria ***Hyperextensibility of the skin ***Widened atrophic scars ***Joint hypermobility ****Can lead to osteoarthritis in the 3rd or 4th decade **Other features ***Poor wound healing ***½ of affected individuals are delivered up to 1 month premature due to premature rupture of fetal membranes ***Some have cardiac abnormalities ****Mitral valve prolapse ****Aortic root dilation with occasional rupture ***Scoliosis ***Pes planus (flatfoot) ***Molluscoid pseudotumors (calcified hematomas) may be associated with scars **Inheritance ***Autosomal dominant single-gene disorder **Etiology ***A major cause is mutations in type V collagen ***At least 3 loci are involved **Biochemical Defects ***Thickened collagen fibrils in skin as well as "cauliflower" deformities of collagen fibrils ***Mutations in COL5A1 and COL5A2 have been seen in some families **Testing ***No biochemical or molecular based testing methods have been devised to provide reliable results *Hypermobility Type (Type III) **Primary characteristics ***Hyperextensibility of large and small joints ***Soft, velvety skin **Other features ***May have normal scarring but stretchy skin ***Dilatation and/or rupture of the ascending aorta ***Scoliosis ***Pes planus **Inheritance ***Autosomal dominant single-gene disorder **Diagnosis is clinical *Vascular Type (Type IV) **Major diagnostic criteria ***Characteristic facial appearance ***Thin, delicate, "pinched" nose ***Thick lips ***Hollow cheeks ***Some have staring appearance due to decreased adipose tissue below the eyes ***Thin, translucent skin ****In fair-skinned individuals, subcutaneous vasculature is easily visible beneath the skin ***Arterial/intestinal/uterine fragility or rupture which can be life threatening ***Extensive bruising **Other characteristics ***Normal scar formation ***May be increased incidence of stroke ***Acrogeria (aged appearance to extremities, particularly hands) ***¼ of affected individuals experience a significant medical problem by age 20 ***Median age of death is 48 years old **Inheritance ***Autosomal dominant as demonstrated by linkage analysis **Etiology (COL3A1 gene) ***Dominant mutations in the gene for the pro-alpha 1 chain of type II collagen ***Caused by abnormal synthesis, structure, or secretion of type II collagen ***50% have new disease-causing mutations ***Over 250 COL3A1 disease-causing mutations have been found **Testing ***Can be reliably accomplished by analysis of type III procollagen and collagen chains harvested from cultured dermal fibroblasts *Kyphoscoliosis type (type VI) **Key features ***Neonatal onset of joint laxity ***Kyphoscoliosis (lateral curvature of the spine accompanying an anteroposterior hump) ***Muscle hypotonia **Other features ***Ocular fragility ***Skin fragility ***Easy bruisability ***Dermal hyperextensibility ***Risk for arterial rupture ***Most have radiologically detectable osteopenia (decreased bone density), but pathological fractures are rare ***Intelligence is normal ***Lifespan may be normal **Etiology ***Caused by deficient activity of the enzyme procollagen lysine hydroxylase **Inheritance ***Autosomal recessive **Testing ***Diagnosis depends on demonstration of increased ratio of deoxypyridinoline to pyridinoline crosslinks in urine measured by HPLC ***Mutation analysis of the PLOD gene that encodes the enzyme procollagen lysine hydroxylase is available on a research basis ***Carrier testing is not available *Arthrochalasia type (types VIIA, VIIB) **Major criteria ***Severe generalized joint hypermobility ***Congenital bilateral hip dislocations that are difficult to repair surgically **Other features ***Tissue fragility including atrophic scars ***Kyphoscoliosis ***Skin hyperextensibility **Etiology ***Caused by a failure to accomplish normal cleavage of the amino-terminal propeptide of type I collagen in all tissues ***Mutations that remove exon 6 in COL1A1 and COL1A2 are seen **Inheritance ***Autosomal dominant **Testing ***Demonstration of exon 6 skipping in cDNAs of COL1A1 or COL1A2 followed by mutational analysis *Dermatosporaxis type (type VIIC) **Very rare form of EDS **Diagnostic Features ***Dermal fragility: the skin is lax but not stretchy **Other features ***Joint dislocation is usually not a feature ***Infants have been reported with premature rupture of membranes and umbilical/inguinal hernias **Etiology ***Caused by failure to cleave off the amino-terminal propeptide of type I collagen due to deficiency of the procolagen I N-peptidase gene **Inheritance ***Autosomal recessive *Other variants (VIII, V X-linked, X) **Type VIII ***Rare autosomal dominant condition ***Characterized by soft, hyperextensible skin, abnormal scarring, easy bruising, hyperextensible joints and generalized periodontitis ***Resembles type I, but is distinguished by early loss of teeth and characteristic purplish discoloration of scars on the shins ***Molecular basis is unknown ***Not clear if it is truly distinct from classical form **Type V X-linked ***Similar to mild classical type ***X-linked recessive inheritance ***Unknown molecular defect **Type X ***Joint hyperextensibility, mitral valve prolapse, easy bruising, poor wound healing, clotting disorder ***Clotting studies showed a defect in the platelet adhesion that is normally observed in response to exposure of platelets to collagen ***May be caused by a defect in fibronectin Management and Treatment *Pregnancy **All cases should be referred to high-risk obstetric practice **Prematurity is a concern **Cervical incompetence can be treated with bed rest and the Trendelenburg position *Musculoskeletal **P/T can improve strength of muscles surrounding lax joints **Surgical procedures can correct dislocation **Intervention for pain management is necessary **An exercise program can strengthen muscles and stabilize joints *Cardiovascular **Enlarged aortic root can be treated with beta blockers but the efficacy or length of treatment is currently unknown **Exercise limitation may be necessary, especially competitive sports **Surgical complications and intraoperative problems are common *Dermatologic **Plastic surgery can be done to close facial wounds or other aesthetically significant areas **Retention sutures tied at a distance from the incision may help support the skin during scar formation Psychosocial Issues *Self esteem **scars, bruising, scoliosis *Financial concerns? *Guilt at passing on mutation *Pain management issues *support network? **family? friends? church? Support Groups and Resources *Ehlers-Danlos National Foundation :800-956-2902 :http//:www.ednf.org *Ehlers-Danlos Support Group :http//:www.ehlers-danlos.org *Family Village :http//:www.familyvillage.wisc.edu/lib_e-ds.htm References *www.geneclinics.org *Management of Genetic Syndromes (Allanson and Cassidy) *OMIM #130000, #130010, #130020, #130050, #305200, #225400, #130060, #130080 Notes The information in this outline was last updated in 2002. This material has been imported fom the wikibook "Genetic counseling"[ http://en.wikibooks.org/wiki/Genetic_counseling] under the GNU Free Documentation License.